Protein–protein recognition and interaction hot spots in an antigen–antibody complex: Free energy decomposition identifies “efficient amino acids”

Authors

  • Virginie Lafont,

    1. Structural Biology and Genomics Department, UMR 7104, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / ULP, F-67404 Illkirch Cedex, France
    2. UMR7175-LC1 CNRS / ULP, ESBS, Parc d'Innovation, 67412 Illkirch Cedex, France
    Current affiliation:
    1. Virginie Lafont's current address is Department of Biology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218-2685
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  • Michael Schaefer,

    1. Laboratoire de Chimie Biophysique, Institut le Bel, Université Louis Pasteur, 67000 Strasbourg, France
    Current affiliation:
    1. Michael Schafer's current address is Novartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland
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  • Roland H. Stote,

    1. Laboratoire de Biophysicochime Moléculaire, Institut de Chimie, LC3-UMR7177, Université Louis Pasteur, 67070 Strasbourg Cedex, France
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  • Danièle Altschuh,

    1. UMR7175-LC1 CNRS / ULP, ESBS, Parc d'Innovation, 67412 Illkirch Cedex, France
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  • Annick Dejaegere

    Corresponding author
    1. Structural Biology and Genomics Department, UMR 7104, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / ULP, F-67404 Illkirch Cedex, France
    • Annick Dejaegere. Structural Biology and Genomics Department, UMR 7104, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, F-67404 Illkirch Cedex, France
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Abstract

The molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) method was applied to the study of the protein–protein complex between a camelid single chain variable domain (cAb-Lys3) and hen egg white lysozyme (HEL), and between cAb-Lys3 and turkey egg white lysozyme (TEL). The electrostatic energy was estimated by solving the linear Poisson–Boltzmann equation. A free energy decomposition scheme was developed to determine binding energy hot spots of each complex. The calculations identified amino acids of the antibody that make important contributions to the interaction with lysozyme. They further showed the influence of small structural variations on the energetics of binding and they showed that the antibody amino acids that make up the hot spots are organized in such a way as to mimic the lysozyme substrate. Through further analysis of the results, we define the concept of “efficient amino acids,” which can provide an assessment of the binding potential of a particular hot spot interaction. This information, in turn, can be useful in the rational design of small molecules that mimic the antibody. The implications of using free energy decomposition to identify regions of a protein–protein complex that could be targeted by small molecules inhibitors are discussed. Proteins 2007. © 2007 Wiley-Liss, Inc.

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